Ishikawa, C. | bioRxiv Science

bioRxiv2022

Chronic inflammation suppresses del(5q)-like MDS HSCs via p53

Inflammation is associated with the pathogenesis of Myelodysplastic syndromes (MDS). Emerging evidence suggests that MDS hematopoietic stem and progenitor cells (HSPCs) exhibit an altered response to systemic low-grade inflammation, which contributes to their competitive advantage over wild-type HSPCs and ensuing hematopoietic defects. Deletion of the long arm of chromosome 5 (del(5q)) is the most common chromosomal abnormality in patients with MDS. Although this subtype of MDS contains several haploinsufficient genes that directly impact innate immune signaling, the effects of an inflammatory milieu on del(5q) MDS HSPCs remains poorly defined. Utilizing a model of del(5q)-like MDS, wherein two 5q genes, miR-146a and TIFAB, are deleted, we found that chronic low-grade inflammation impaired the function of del(5q)-like MDS HSPCs and contributed to a more severe disease. The del(5q)-like MDS HSPCs exposed to chronic inflammation became less quiescent, but without changes in cell viability. In response to inflammation, mouse and human del(5q) MDS HSPCs activated a partial p53 response. The impaired function and reduced cellular quiescence of del(5q) MDS HSPCs exposed to inflammation could be restored by deletion of p53. Since TP53 mutations are highly enriched in del(5q) AML patients following an initial MDS diagnosis, increased p53 activation in del(5q) MDS HSPCs due to inflammation may create a selective pressure for genetic inactivation of p53. These findings uncover the contribution of systemic inflammation on dyshematopoiesis in del(5q) MDS and provide a potential explanation for acquired p53 mutations in myeloid malignancies with del(5q).

cancer biology↗

bioRxiv2020

Transcriptome analysis of sevoflurane exposure effects at the different brain regions

BackgroundsSevoflurane is a most frequently used volatile anaesthetics, but its molecular mechanisms of action remain unclear. We hypothesized that specific genes play regulatory roles in whole brain exposed to sevoflurane. Thus, we aimed to evaluate the effects of sevoflurane inhalation and identify potential regulatory genes by RNA-seq analysis. MethodsEight-week old mice were exposed to sevoflurane. RNA from four medial prefrontal cortex, striatum, hypothalamus, and hippocampus were analysed using RNA-seq. Differently expressed genes were extracted. Their gene ontology terms and the transcriptome array data of the cerebral cortex of sleeping mice were analysed using Metascape, and the gene expression patterns were compared. Finally, the activities of transcription factors were evaluated using a weighted parametric gene set analysis (wPGSA). JASPAR was used to confirm the existence of binding motifs in the upstream sequences of the differently expressed genes. ResultsThe gene ontology term enrichment analysis result suggests that sevoflurane inhalation upregulated angiogenesis and downregulated neural differentiation in the whole brain. The comparison with the brains of sleeping mice showed that the gene expression changes were specific to anaesthetized mice. Sevoflurane induced Klf4 upregulation in the whole brain. The transcriptional analysis result suggests that KLF4 is a potential transcriptional regulator of angiogenesis and neural development. ConclusionsKlf4 was upregulated by sevoflurane inhalation in whole brain. KLF4 might promote angiogenesis and cause the appearance of undifferentiated neural cells by transcriptional regulation. The roles of KLF4 might be key to elucidating the mechanisms of sevoflurane induced functional modification in the brain.

genetics↗